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Observational Study
. 2020 Feb 25;19(1):25.
doi: 10.1186/s12933-020-00999-5.

The risk of sudden cardiac arrest and ventricular arrhythmia with rosiglitazone versus pioglitazone: real-world evidence on thiazolidinedione safety

Charles E Leonard  1 , Colleen M Brensinger  2 , Ghadeer K Dawwas  2 , Rajat Deo  2   3 , Warren B Bilker  2 , Samantha E Soprano  2 , Neil Dhopeshwarkar  2 , James H Flory  2   4 , Zachary T Bloomgarden  5 , Joshua J Gagne  6 , Christina L Aquilante  7 , Stephen E Kimmel  2   3 , Sean Hennessy  2   8
Affiliations
Observational Study

The risk of sudden cardiac arrest and ventricular arrhythmia with rosiglitazone versus pioglitazone: real-world evidence on thiazolidinedione safety

Charles E Leonard et al. Cardiovasc Diabetol. .

Abstract

Background: The low cost of thiazolidinediones makes them a potentially valuable therapeutic option for the > 300 million economically disadvantaged persons worldwide with type 2 diabetes mellitus. Differential selectivity of thiazolidinediones for peroxisome proliferator-activated receptors in the myocardium may lead to disparate arrhythmogenic effects. We examined real-world effects of thiazolidinediones on outpatient-originating sudden cardiac arrest (SCA) and ventricular arrhythmia (VA).

Methods: We conducted population-based high-dimensional propensity score-matched cohort studies in five Medicaid programs (California, Florida, New York, Ohio, Pennsylvania | 1999-2012) and a commercial health insurance plan (Optum Clinformatics | 2000-2016). We defined exposure based on incident rosiglitazone or pioglitazone dispensings; the latter served as an active comparator. We controlled for confounding by matching exposure groups on propensity score, informed by baseline covariates identified via a data adaptive approach. We ascertained SCA/VA outcomes precipitating hospital presentation using a validated, diagnosis-based algorithm. We generated marginal hazard ratios (HRs) via Cox proportional hazards regression that accounted for clustering within matched pairs. We prespecified Medicaid and Optum findings as primary and secondary, respectively; the latter served as a conceptual replication dataset.

Results: The adjusted HR for SCA/VA among rosiglitazone (vs. pioglitazone) users was 0.91 (0.75-1.10) in Medicaid and 0.88 (0.61-1.28) in Optum. Among Medicaid but not Optum enrollees, we found treatment effect heterogeneity by sex (adjusted HRs = 0.71 [0.54-0.93] and 1.16 [0.89-1.52] in men and women respectively, interaction term p-value = 0.01).

Conclusions: Rosiglitazone and pioglitazone appear to be associated with similar risks of SCA/VA.

Keywords: Cardiac arrhythmias; Cohort studies; Medicaid; Pharmacoepidemiology; Propensity score; Sudden cardiac death; Thiazolidinediones; Type 2 diabetes mellitus.

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Conflict of interest statement

CEL serves on the Executive Committee of and SH directs the University of Pennsylvania’s Center for Pharmacoepidemiology Research and Training. The Center receives unrestricted support for education from Pfizer. JHF has consulted for Boehringer Ingelheim, Eli Lilly and Company, and Genentech. JJG has received salary support from grants from Eli Lilly and Company and Novartis to the Brigham and Women’s Hospital, and was a consultant to Aetion Inc. and Optum Inc., all for unrelated work. SEK has consulted for pharmaceutical companies, unrelated to this work. SH has consulted for GlaxoSmithKline on matters unrelated to this work. All other authors report no competing interests.

Figures

Fig. 1
Fig. 1
Kaplan–Meier curve depicting the probability of sudden cardiac arrest/ventricular arrhythmia upon new use of rosiglitazone vs. pioglitazone, limited to the propensity score-matched sample in Medicaid (N = 379,598). Solid line is pioglitazone. Dashed line is rosiglitazone. p-value for stratified log-rank test = 0.75
Fig. 2
Fig. 2
Confounder-adjusted marginal hazard ratios for rosiglitazone (vs. pioglitazone) exposure and primary and secondary outcomes, by dataset | Medicaid and Optum. HR hazard ratio. Squares depict hazard ratios for the primary outcome of sudden cardiac arrest and ventricular arrhythmia. The circle depicts a hazard ratio for the secondary outcome of sudden cardiac death and fatal ventricular arrhythmia. * Optum was the prespecified conceptual replication dataset. Its analyses were limited to the primary outcome since the dataset does not document deaths
See this image and copyright information in PMC

References

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